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PDBsum entry 3d7h
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References listed in PDB file
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Key reference
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Title
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Interactions between human glutamate carboxypeptidase ii and urea-Based inhibitors: structural characterization.
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Authors
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C.Barinka,
Y.Byun,
C.L.Dusich,
S.R.Banerjee,
Y.Chen,
M.Castanares,
A.P.Kozikowski,
R.C.Mease,
M.G.Pomper,
J.Lubkowski.
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Ref.
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J Med Chem, 2008,
51,
7737-7743.
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PubMed id
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Abstract
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Urea-based, low molecular weight ligands of glutamate carboxypeptidase II
(GCPII) have demonstrated efficacy in various models of neurological disorders
and can serve as imaging agents for prostate cancer. To enhance further
development of such compounds, we determined X-ray structures of four complexes
between human GCPII and urea-based inhibitors at high resolution. All ligands
demonstrate an invariant glutarate moiety within the S1' pocket of the enzyme.
The ureido linkage between P1 and P1' inhibitor sites interacts with the
active-site Zn(1)(2+) ion and the side chains of Tyr552 and His553. Interactions
within the S1 pocket are defined primarily by a network of hydrogen bonds
between the P1 carboxylate group of the inhibitors and the side chains of
Arg534, Arg536, and Asn519. Importantly, we have identified a hydrophobic pocket
accessory to the S1 site that can be exploited for structure-based design of
novel GCPII inhibitors with increased lipophilicity.
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